CD8 T Cells in Rheumatoid Arthritis

尽管抗细胞因子治疗取得了进展，但类风湿性关节炎（RA）的治疗仍然需要 持续和积极的免疫抑制，有严重副作用的风险。该提案旨在 探讨CD 8 + CD 28 ~ CD 56 + T抑制细胞抑制类风湿性滑膜炎的机制 以及如何将它们开发成一种新的过继性免疫疗法来治疗这种严重的疾病 利用人滑膜-NOD-SCID嵌合体的临床前模型，我们已经鉴定了过继性的 转移CD 8 + CD 28 ~ CD 56 + T细胞克隆作为抑制滑膜炎的有效手段。体内和体外 这样的CD 8 + CD 28-CD 56 + Ts细胞下调共刺激分子CD 86的表达， 滑膜成纤维细胞和其他滑膜APC。在这里，我们假设CD 8 * CD 28-CD 56 + T细胞诱导 RA滑膜病变中CD 4 T细胞对APC耐受的无反应性。导致长期 抑制疾病。具体目标1旨在确定分子机制， CD 8 + CD 28 ~ CD 56 + Ts细胞调节APC诱导CD 4 T细胞无反应性。具体目标2将 检查条件APC如何与CD 4 T细胞相互作用，成熟的免疫突触是否 诱导以及CD 4 T细胞中的跨膜信号传导事件如何不同于正常活化。在 特别是，我们将检查这种CD 4 T细胞是否具有增强的无反应性T细胞的特征。 特定信号蛋白的蛋白水解降解在具体目标3中，我们建议寻找关键的 将免疫抑制能力传递到CD 8 + CD 28 ~ CD 56 + T细胞上的分子和途径， 包括对CD 56分子本身作用的研究。在具体目标4中，我们将探讨这些 特异性CDS T细胞作为生物标志物在预测疾病进程和预后中具有前瞻性价值。 随访早期RA患者。 相关性：风湿性关节炎是一种由免疫系统介导的致残性疾病。可以 治疗但未治愈，对于受影响的个人和社会来说代价高昂。免疫系统拥有 天然抑制免疫介导的炎症的细胞。本提案的目标是了解如何 这些抗炎淋巴细胞的功能以及如何将它们作为新的治疗试剂加以利用 在RA中。

Despite progress in anti-cytokine therapy the management of rheumatoid arthritis (RA) still requires continuous and aggressive immunosuppression, with a risk for severe side effects. This proposal is designed to explore the mechanisms through which CD8+CD28~CD56+ T suppressor cells inhibit rheumatoid synovitis and how they can be developed into a novel adoptive immunotherapy for this crippling disease Exploiting the preclinical model of human synovium-NOD-SCID chimeras we have identified the adoptive transfer of CD8+CD28~CD56+ T cell clones as a potent means of suppressing synovitis. In vivo and in vitro such CD8+CD28"CD56+ Ts cells downregulate the expression of the costimulatory molecule CD86 on synovial fibroblasts and other synovial APC. Here we hypothesize that CD8*CD28"CD56+ T cells induce unresponsiveness of CD4 T cells by tolerizinq APC in the synovial lesions of RA. leading to long-term inhibition of the disease. Specific Aim 1 is designed to identify the molecular mechanisms through which CD8+CD28~CD56+ Ts cells condition APCs to induce CD4 T cell unresponsiveness. Specific Aim 2 will examine how conditioned APC interact with CD4 T cells, whether a mature immunological synapse is induced and how transmembrane signaling events in CD4 T cells are different from normal activation. In particular, we will examine whether such CD4 T cells have the signature of anergic T cells with enhanced proteolytic degradation of specific signaling proteins In Specific Aim 3 we propose to seek for the critical molecules and pathways that convey immunosuppressive capability onto CD8+CD28~CD56+ T cells, including studies on the role of the CD56 molecule itself. In Specific Aim 4 we will explore whether these specialized CDS T cells have value as biomarkers in predicting disease course and outcome in prospectively followed patients with early RA. Relevance: Rheumatoid arthritis is a crippling disease that is mediated by the immune system. It can be treated but not cured and is costly for the affected individual and society. The immune system possesses cells that naturally inhibit immune-mediated inflammation. The goal of this proposal is to understand how such anti-inflammatory lymphocytes function and how they can be harnessed as novel therapeutic reagents in RA.